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Asymchem Continuous Ethynyl-Grignard Reagent Production Platform
2020-01-21 16:31

Organic synthesis plays an important role in drug research and development. Whether the molecular structure of drug candidates can be synthesized quickly and efficiently determines the time for bringing a new drug to market. If the synthesis process of complex organic molecules is regarded as a construction project, the effective use of molecular units with certain functional groups for splicing is just like the construction of high-rise buildings using various blocks for assembly. Those molecular units are called Building Blocks. Building Blocks, known as the cornerstones of drug molecules, are an indispensable part of drug molecular synthesis process from drug discovery to commercial production.

Scale synthesis of Building Blocks adopting a safer, more reliable and environmentally friendly process will start a new chapter for the drug industry. Asymchem Laboratories Co., Ltd. (SHE: 002821. SZ, hereinafter referred to as “Asymchem”) has developed multiple Building Block continuous reaction technology manufacturing platforms by virtue of years of exploration and practice in the field of continuous reaction technology, which solved many safety and environmental concerns in the production of API raw materials. These new processes have been applied to downstream products of several large European and American multinational pharmaceutical companies in production.

Ethynyl-Grignard reagent is a typical and widely used Building Block compound, which is generally prepared from reaction of acetylene gas and alkyl Grignard reagents. Acetylene is one of the most common, simple and economical organic chemical raw material with very active triple carbon-carbon bond, from which thousands of organic compounds can be derived. However, due to its active nature, acetylene is a highly flammable and explosive gas, which can hardly be applied on a large scale. Even if small batch reaction could be carried out, the reaction process would be difficult to control.

In the traditional batch production of Ethynyl-Grignard reagents, acetylene gas must be dissolved in a solvent to keep stable. As its chemical equilibrium is greatly affected by temperature changes, a low temperature environment of the system must be maintained. Once encountering disturbance (such as stirring) or heating up, a large amount of acetylene gas will be released, which greatly threatens the safety of the system. However, Alkyl Grignard reagent should be dripped slowly to the solvent while continuously adding excess acetylene to ensure an effective reaction. Due to the dangerous characteristics of acetylene, it is rather difficult to control the whole gas-liquid reaction system, making large-scale production more difficult to achieve.   

In addition, in terms of production cycle and operation, there are also many problems in traditional batch reactions. The heat release of Grignard reactions is usually large, so it is necessary to control the dripping acceleration of halohydrocarbon to reduce the side reaction, resulting in a longer production cycle of of batch reactions. Meanwhile, water- and air-sensitive Grignard reagents cause higher risk in storage cost, if not used in a timely manner after preparation.

In view of the difficulties of these traditional batch reactions, Asymchem has designed continuous reactors with independent intellectual property rights and developed new processes for continuous manufacturing of Ethynyl-Grignard reagents. A greener, safer and more reliable end-to-end process has been realized and applied to the whole process from the dissolution of acetylene to the preparation of Ethynyl-Grignard reagents. The new process has broken through the safety bottleneck restricting the scale use of the highly explosive acetylene gas, and realized a risk-free and continuous production of acetylene, which can be prepared at any time. 

In the continuous production of Ethynyl-Grignard reagents, liquid raw materials and acetylene gas are injected into the continuous reaction device, and the exhaust gas and products are discharged from the reaction device continuously. When the operation reaches a steady state, the residence time of any cross-section material particles in the device is the same, and there is no mixing of particles with different residence time. Through the precise control of the reaction parameters, the amount of gas is apportioned by time in the continuous reaction process and is relatively stable in any period of time, so that the raw materials can be fully mixed and reacted. The injected acetylene gas is also consumed in time, which significantly shortens the retention time of the acetylene solution, thus effectively improving the safety of manufacturing process. 

Asymchem has realized automated control throughout the process, requiring less operators and shorter production cycle. Compared to batch reactions, the utilization rate of acetylene gas is doubled, thus the emission is significantly decreased, which contributes to a friendlier environment. Meanwhile, the continuous production of Ethynyl-Grignard reagents avoids the long-term storage of raw materials, further reducing the storage cost. 

A variety of pharmaceutical intermediates can be derived from Ethynyl-Grignard reagents as core units through simple chemical reactions, typically including trimethylsilylacetylene (TMSA), propiolic acids, and alkynyl compounds such as alkynyl alkane and alkynol, etc.

TMSA is an essential synthetic unit in the preparation of various monoalkynes and polyalkynes, which is widely used in heterocyclic chemistry and carbon-carbon coupling reactions. The difficulty of scale-up and long production cycle are always the difficulties that restrict the scale production of TMSA in batch production process. Asymchem has successfully developed the continuous TMSA production platform, through which end-to-end manufacturing and post-processing can be completed by directly charging the ethynyl-grignard reagents to the next continuous reaction module to react with trimethylchlorosilane. The total yield is 15-20% higher than that of batch production process.     

A continuous Ethynyl-Grignard manufacturing platform is just one example of Asymchem’s numerous continuous flow technology platforms. As a pioneer and practitioner in the field of continuous reaction technology and through years of R&D investment and technology advances, Asymchem is committed to promoting the innovation and commercial application of green technology, serving the R&D and production of new drugs, and achieving the sustainable development goals of the industry.

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  • Morrisville NC 27560 USA
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  • 600 Airport Blvd., Suite 1000 Morrisville, NC 27560 USA
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